Barth syndrome is an X-linked disorder that can result from defects in the gene encoding tafazzin, an acyltransferase that can modify cardiolipin to a tetralinoleoyl form and that can be involved in mitochondrial respiration. The clinical manifestations of Barth syndrome may include, but are not limited to, muscular hypotonia, cardiomyopathy, and neutropenia.
In Barth syndrome, a single gene mutation in the mitochondrial transacylase, TAZ, can result in impairment of lipid metabolism (see Aprikyan A A and Khuchua Z, Brit J Haematol, 2013; 161(3):330-8) leading to mitochondrial dysfunction, which is manifested clinically in highly energetic tissues such as the heart and skeletal muscle (see Aprikyan A A and Khuchua Z, Brit J Haematol, 2013; 161(3):330-8 and Khuchua Z, et al., Circ Res, 2006; 99(2):201-8). TAZ can catalyze the transfer of acyl chains from phosphatidyl choline to cardiolipin (CL), remodeling monolysocardiolipin (MLCL) to tetralinoleoyl cardiolipin (L4CL) (see Houtkooper R H, et al., Biochim Biophys Acta, 2009; 1788(10):2003-14 and Xu Y, et al., J Biol Chem, 2003; 278(51):51380-5). Barth syndrome patients exhibit a reduction in the levels of L4CL and an accumulation of MLCL (see Xu Y, et al. J Biol Chem, 2006; 281(51):39217-24), which can lead to mitochondrial dysfunction. These patients may experience growth deficiencies, exercise intolerance, cardiomyopathy, hypotonia, neutropenia, etc. (see Barth P G, et al., Am J Med Genet Part A, 2004; 126A(4):349-54).
One of the leading causes of morbidity among Barth syndrome patients is cardiac failure. Patients may exhibit endomyocardial fibroelastosis, dilated cardiomyopathy, and, as often observed with mitochondrial disorders, hypertrabeculation. At the cellular level, hearts from affected patients may demonstrate morphologically abnormal mitochondria (see Neustein H B, et al., Pediatrics, 1979; 64(1):24-9) while fibroblasts may demonstrate a deficiency of respiratory complexes (see Barth P G, et al., J Inherit Metab Dis, 1999; 22(4):555-67) and a decrease in oxygen consumption rates (see Houtkooper R H, et al., Biochim Biophys Acta, 2009; 1788(10):2003-14). CL, a structurally unique phospholipid component of the inner mitochondrial membrane, can provide functional support for the electron transport chain complexes (see Kiebish M A, et al., J Lipid Res, 2013; 54(5):1312-25 and Pfeiffer K, et al., J Biol Chem, 2003; 278(52):52873-80). In the absence of CL, respiratory supercomplex formation may be hindered (McKenzie M, et al., J Mol Biol, 2006; 361(3):462-914) and individual complex activity may be decreased (see Zhang M, et al., J Biol Chem, 2005; 280(33):29403-8). Disturbances in the acyl chain composition of CL have been linked to impaired mitochondrial respiratory function (see Xu Y, et al., J Biol Chem, 2003; 278(51):51380-5), possibly through alteration in membrane dynamics (see Baile M G, et al., J Biol Chem, 2014; 289(3): 1768-78).
Since mitochondrial respiration is responsible for ATP generation, it has long been assumed that the cardiac and skeletal myopathy seen in Barth syndrome is a result of diminished ATP generation and depleted ATP stores. Recently, it has been reported that cardiomyocytes (CMs) derived from induced pluripotent stem cells (iPS cells) containing targeted TAZ mutations demonstrate normal ATP stores but increased reactive oxygen species (ROS), suggesting that the pathogenesis of Barth syndrome may be due to ROS generation (see Wang G, et al., Nat Med, 2014; 20(6):616-23). ROS have long been implicated in the pathogenesis of cardiac hypertrophy and regulation of excitation-contraction coupling through effects on specific signaling pathways such as ERK, AKT, and PKA (see Sag C M, et al., J Mol Cell Cardiol, 2014; 73C:103-11). Mitochondrial ROS, in particular, have been associated with angiotensin II-induced hypertrophy and heart failure associated with Gaq signaling (see Dai D F, et al., Circ Res 2011; 108(7):837-46). Excessive ROS have also been linked to apoptosis (see Murphy M P, et al., Cell Metab, 2011; 13(4):361-6).
Additionally, there are other indications associated with a tafazzin deficiency and remodeled cardiolipin deficiency. These indications include, but are not limited to, dilated cardiomyopathy, hypertrophic cardiomyopathy, noncompaction cardiomyopathy, ischemic cardiomyopathy, hypertensive cardiomyopathy, diabetic cardiomyopathy, and chemotherapy induced cardiomyopathy. The mitochondrial phospholipid cardiolipin can be involved in optimal, or substantially optimal, mitochondrial respiration, and loss of mitochondrial phospholipid cardiolipin can be associated with the development of heart failure (see Sparagna G C, et al., J Lipid Res, 2007; 48(7):1559-70).